Aminoalkyl-1,1-diphosphonic acid derivatives (hereinafter called by the general term bisphosphonates) are important pharmaceutical agents in the treatment of bone diseases and some disturbances of calcium metabolism such as hyper-calcaemia, osteoporosis, tumor osteolysis, Paget's disease, etc.
Bisphosphonates as pharmaceutical agents are described, for example, in EP-A-170,228; EP-A-197,478; EP-A-22,751; EP-A-252,504; EP-A-252,505; EP-A-258,618; EP-A-350,002; EP-A-273,190; and WO-A-90/00798, each of which are incorporated herein by reference.
Pharmaceutical forms of currently marketed bisphosphonates are oral formulations (tablets or capsules) or solutions for intravenous injection or infusion. They are systemically well-tolerated when administered at therapeutic doses. However, bisphosphonates as a class are irritant to skin and mucous membranes, and when given orally on a continuous basis, may result in digestive tract side effects, e.g., esophageal adverse events or gastrointestinal disturbances. As a consequence, and due to their low oral bioavailability, the oral route of administration has, to date, to follow inconvenient recommendations of use for the patient.
As described, bisphosphonates are accepted as providing strong efficacy in the management of osteoporosis. However, given the administration restrictions related to low oral bioavailability and potential for gastrointestinal side effects, there is a clear opportunity for regimens which offer improved convenience and flexibility, leading to a higher level of compliance and superior patient management/satisfaction.
Furthermore, it has been found in the ibandronate clinical development program, that ibandronate showed fracture reduction efficacy with a drug-free interval beyond daily administration. It was quite unexpected that fracture reduction benefit could be derived from a weekly or monthly administration of an oral bisphosphonate with a single or multiple tablet administration scheme.